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Association of the forced oscillation technique with negative expiratory pressure in COPD
Respiratory Physiology & Neurobiology 220 (2016) 62–68
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Association of the forced oscillation technique with negative expiratory pressure in COPD Takefumi Akita a , Toshihiro Shirai a,∗,1 , Kazutaka Mori b , Yukiko Shimoda a , Takahito Suzuki a , Ichiro Hayashi a , Rie Noguchi a , Eisuke Mochizuki a , Shogo Sakurai a , Mika Saigusa a , Taisuke Akamatsu a , Akito Yamamoto a , Yuichiro Shishido a , Satoru Morita a , Kazuhiro Asada a , Takafumi Suda b a b
Department of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, Japan Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
a r t i c l e
i n f o
Article history: Received 28 August 2015 Received in revised form 8 September 2015 Accepted 10 September 2015 Available online 11 September 2015 Keywords: Expiratory flow limitation Forced oscillation technique Negative expiratory pressure Reactance Tidal breathing
a b s t r a c t Expiratory flow limitation (EFL) during tidal breathing is common in patients with severe COPD, and a major determinant of dynamic hyperinflation and exercise limitation. The negative expiratory pressure (NEP) technique has been the gold standard to detect EFL, while the forced oscillation technique (FOT) has also been reported to detect it. However, the association of FOT with NEP is not fully understood. We assessed whether broadband frequency FOT would predict the presence of EFL measured by NEP. FOT, NEP, and spirometry were performed in 51 patients with COPD. The extent of emphysema was measured by high-resolution computed tomography and scored. Fifteen patients were classified into the EFL-positive group and 36 into the EFL-negative group. In multivariate logistic regression analysis, EFL was independently predicted by emphysema score, forced vital capacity, and whole-breath respiratory system reactance at 5 Hz (X5). The receiver operator characteristic curve analysis revealed that inspiratory X5 best predicted EFL-positivity. X5-related forced oscillatory parameters are useful for detecting EFL in the management of COPD. © 2015 Published by Elsevier B.V.
1. Introduction
Abbreviations: AIC, Akaike’s information criteria; ALX, low-frequency reactance area; , differences between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEV1, forced expiratory volume in 1 s; FOT, forced oscillation technique; Fres, resonant frequency; FVC, forced vital capacity; HRCT, high-resolution computed tomography; NEP, negative expiratory pressure; ROC, receiver operator characteristic; Rrs, respiratory system resistance; R5, Rrs at 5 Hz; R20, Rrs at 20 Hz; R5-R20, the difference between R5 and R20; X5, Xrs at 5 Hz; Xrs, respiratory system reactance. ∗ Corresponding author at: Shizuoka General Hospital, 4-27-1 Kita-Ando, Aoi, Shizuoka 420−8527, Japan. Fax: +81 54 247 6140. E-mail addresses: [email protected] (T. Akita), [email protected] (T. Shirai), [email protected] (K. Mori), [email protected] (Y. Shimoda), [email protected] (T. Suzuki), [email protected] (I. Hayashi), [email protected] (R. Noguchi), [email protected] (E. Mochizuki), [email protected] (S. Sakurai), [email protected] (M. Saigusa), [email protected] (T. Akamatsu), akito [email protected] (A. Yamamoto), [email protected] (Y. Shishido), [email protected] (S. Morita), [email protected] (K. Asada), [email protected] (T. Suda). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.resp.2015.09.002 1569-9048/© 2015 Published by Elsevier B.V.
Some patients with COPD show overlapped flow-volume curves between tidal breathing and forced expiration. This phenomenon has been taken as an indicator of expiratory flow limitation (EFL), common in patients with severe COPD, and is a major determinant of dynamic hyperinflation and exercise limitation (Koulouris and Hardavella, 2011). EFL occurs when an increase in transpulmonary pressure causes no increase in expiratory flow. The negative expiratory pressure (NEP) technique has been the gold standard for detecting EFL (Koulouris et al., 2012). In the absence of EFL, the increase in pressure gradient between the alveoli and the airway opening caused by NEP results in increased expiratory flow, whereas in patients with EFL, application of NEP does not change the expiratory flow. This method is simple, noninvasive, and does not require forced expiration, collaboration on the part of the patient, or use of body plethysmography. As another approach, Dellacà et al. indicated that the differences between the inspiratory and expiratory phases of respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) allowed the detection of EFL (Dellacà et al., 2004). It is thought that Xrs normally reflects the elastic and inertial properties of the respiratory
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Fig. 1. Representative examples of flow-volume loops during the negative expiratory pressure (NEP) maneuver for expiratory flow limitation (EFL)-positive (upper left), EFL-negative (lower left), and excluded patients because of indeterminable results (lower right).
system, but with flow limitation, oscillatory signals cannot pass through the choke points and reach the alveoli. During EFL, respiratory system resistance (Rrs) and Xrs reflect the mechanical properties of airways proximal to the choke points, which are much stiffer than the periphery, producing a marked reduction in apparent compliance and a fall in Xrs. Subsequently, Dellacà et al. (2007)
reported a modest agreement between NEP and FOT by using an experimental setup for simultaneous measurements (Dellacà et al., 2007). To date, there has been no other study assessing the association of FOT with NEP. In contrast to the monofrequency FOT at 5 Hz used by Dellacà et al. (2007) clinical application of broadband frequency FOT has progressed recently with the spread of
Fig. 2. Colored 3-dimensional images of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) in representative expiratory flow limitation (EFL)-positive (upper panel) and EFL-negative (lower panel) patients. Respiratory cycle dependence (Rrs was higher and Xrs was more negative in the expiratory phases than in the inspiratory phases) and frequency dependence (Rrs increased at lower frequencies and fell with increasing frequencies) were marked in the EFL-positive patients.
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Table 1 Characteristics of the subjects. Patients with COPD (n = 51)
EFL-positive (n = 15)
EFL-negative (n = 36)
Age (years) Gender (male/female) Body mass index (kg/m2 ) Current/ex/never smoker Pack-years mMRC scale CAT score Emphysema score GOLD I/II/III/IV LAMA LABA LAMA + LABA LAMA + ICS/LABA Sustained-release theophylline FVC (% predicted) FEV1 (% predicted) FEV1/FVC (%) FEF25-75% (% predicted) IC (L)
74 (65–84) 46/5 21.1 (15.1–29.1) 3/48/0/ 50 (2–180) 1 (0–5) 10 (1–35) 10 (2–22) 11/16/17/7 5 6 31 4 9 90.3 (38.3–128.1) 50.9 (16.2–114.2) 50.7 (21.4–68.4) 18.2 (4.9–51.1) 1.81 (0.75–3.03)
74 (67–84) 11/4 21.0 (15.1–29.0) 1/14/0 50 (2–180) 2 (0–5)* 11 (1–22) 12 (2–22)* 0/4/6/5* 1 2 11 1 4 71.6 (38.3–101.7)* 40.8 (16.2–77.3)* 42.9(21.4–64.5) 9.1 (4.9–42.5)* 1.63 (0.75–2.77)*
75 (65–84) 35/1 21.2 (16.2–29.1) 2/34/0 50 (10–150) 1 (0–4) 10 (2–35) 10 (2–22) 11/12/11/2 4 4 20 3 5 95.5 (50.3–128.1) 59.9(27.4–114.2) 52.5 (27.2–68.4) 21.4 (5.3–51.1) 1.95 (0.88–3.03)
R5 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory R5
3.72 (1.73–7.11) 3.35 (1.66–6.57) 4.21 (1.78–9.00) −0.71 (−3.78–0.93)
4.96 (2.70–7.11)* 4.42 (2.88–6.57)* 4.56 (2.52–9.00)* −0.78 (−3.78–0.93)
3.40 (1.73–5.96) 3.25 (1.66–5.46) 3.65 (1.78–7.05) -0.69 (-3.76–0.26)
R20 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory R20
2.74 (1.42–5.43) 2.59 (1.42–4.58) 2.87 (1.41–6.31) −0.27 (−2.17–0.71)
3.23 (1.83–5.43)* 3.29 (1.84–4.58)* 3.00 (1.83–6.31) −0.14 (−1.76–0.71)
2.58 (1.42–4.86) 2.45 (1.42–4.06) 2.80 (1.41–5.66) −0.40 (−2.17–0.23)
R5-R20 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory (R5–R20)
0.98 (0.13–2.38) 0.68 (0.03–2.03) 1.22 (0.22–2.76) −0.41 (−2.02–0.35)
1.55 (0.87–2.38)* 1.29 (0.65–1.99)* 1.81 (0.69–2.76)* −0.63 (−2.02–0.35)
0.80 (0.13–2.04) 0.55 (0.03–2.03) 1.02 (0.22–2.33) −0.35 (−1.59–0.16)
X5 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory X5
−1.28 (−5.30–0.09) −1.06 (−3.13–0.01) −1.69 (−8.39–0.13) 0.51 (−0.79–6.44)
−2.97 (−5.30–1.54)* −1.95 (−2.94–0.74)* −3.38 (−8.39–1.85)* 1.61 (−0.25–6.44)*
−0.80 (−3.67–0.09) −0.76 (−3.13–0.01) −0.75 (−5.99–0.13) 0.14 (−0.79–4.63)
Fres (Hz) Whole-breath Inspiratory Expiratory Fres
14.83 (5.68–25.89) 12.29 (4.94–24.51) 16.63 (5.96–28.70) −2.72 (−14.95–5.57)
20.12 (14.88–25.89)* 19.10 (11.40–23.57)* 22.65 (16.24–28.70)* −4.52 (−11.75–0.24)*
11.60 (5.68–24.25) 11.47 (4.94–24.51) 11.51 (5.96–26.84) −1.37 (−14.95–5.57)
ALX (cmH2 O/L/s x Hz) Whole-breath Inspiratory Expiratory ALX
7.85 (0.35–48.57) 5.31 (0.16–30.08) 11.11 (0.40–77.23) −3.57 (−66.18–5.03)
22.86 (9.34–48.57)* 12.46 (3.50–25.91)* 28.21 (11.87–77.23)* −14.17 (−66.13–1.08)*
3.76 (0.35–31.86) 3.37 (0.16–30.08) 3.43 (0.40–50.54) −0.70 (−42.26–5.03)
Values are shown as the median (range) or numbers. Abbreviations: ALX, low-frequency reactance area; CAT, COPD assessment test; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEF25-75%, forced expiratory flow between 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; Fres, resonant frequency; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroids; LABA, long-acting 2-agonists; LAMA, long-acting antimuscarinic agents; mMRC, modified British Medical Research Council; R5 and R20, respiratory system resistance at 5 ; X5, respiratory system reactance at 5 Hz. * p < 0.05 versus EFL-negative.
commercially available devices. We hypothesized that broadband frequency FOT would predict the presence of EFL measured by NEP. In this cross-sectional study, we assessed the association of FOT with NEP in patients with COPD. 2. Methods
Obstructive Lung Disease (GOLD, 2013) and had been receiving medications, including long-acting antimuscarinic agents, longacting 2-agonists, inhaled corticosteroids, or sustained-release theophylline. They were clinically stable and had no exacerbations, defined as increased dyspnea associated with a change in the quality and quantity of sputum, for at least one month before the study.
2.1. Subjects 2.2. Study design Sixty-three patients with COPD who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between January 2014 and January 2015 were enrolled in this study. The patients satisfied the definition of the Global Initiative for Chronic
On the same examination day, when their clinical symptoms were stable, measurements of respiratory impedance using FOT, NEP, and pulmonary function tests were performed in that order.
T. Akita et al. / Respiratory Physiology & Neurobiology 220 (2016) 62–68 Table 2 Univariate analysis for predictors of EFL-positivity.
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2.3. Modified Medical Research Council (mMRC) and COPD assessment test (CAT)
Variables
Odds ratio
95% CI
p-Value
Age (years) Body mass index (kg/m2 ) Pack-years mMRC scale CAT score Emphysema score %FVC (% predicted) %FEV1 (% predicted) FEF25–75% (% predicted) IC (L) Whole-breath R5 (cmH2 O/L/s) Inspiratory R5 (cmH2 O/L/s) Expiratory R5 (cmH2 O/L/s) R5 (cmH2 O/L/s) Whole-breath R20 (cmH2 O/L/s) Inspiratory R20 (cmH2 O/L/s) Expiratory R20 (cmH2 O/L/s) R20 (cmH2 O/L/s) Whole-breath R5–R20 (cmH2 O/L/s) Inspiratory R5–R20 (cmH2 O/L/s) Expiratory R5–R20 (cmH2 O/L/s) (R5–R20) (cmH2 O/L/s) Whole-breath X5 (cmH2 O/L/s) Inspiratory X5 (cmH2 O/L/s) Expiratory X5 (cmH2 O/L/s) X5 (cmH2 O/L/s) Fres (Hz) Inspiratory Fres (Hz) Expiratory Fres (Hz) Fres (Hz) ALX (cmH2 O/L/s x Hz) Inspiratory ALX (cmH2 O/L/s x Hz) Expiratory ALX (cmH2 O/L/s x Hz) ALX (cmH2 O/L/s x Hz)
1.006 1.575 1.003 1.913 1.016 1.110 0.928 0.943 0.906 0.243 2.371 3.656 1.694 1.029 2.049 3.272 1.497 1.910 40.902 24.036 13.877 0.444 0.225 0.071 0.437 2.010 1.475 1.415 1.329 0.868 1.160 1.266 1.087 0.933
0.894–1.132 0.998–2.893 0.986–1.020 1.112–3.588 0.935–1.102 0.990–1.259 0.879–0.966 0.900–0.977 0.829–0.968 0.057–0.816 1.414–4.499 1.844–9.045 1.153–2.654 0.552–2.026 1.073–4.233 1.468–8.524 0.888–2.614 0.652–7.092 7.086–457.026 4.958–194.777 3.745–82.651 0.109–1.632 0.083–0.453 0.011–0.246 0.248–0.659 1.317–3.428 1.223–1.943 1.192–1.794 1.155–1.629 0.740–1.001 1.080–1.283 1.125–1.510 1.042–1.152 0.885–0.972
0.9221 0.0799 0.6886 0.0269 0.6884 0.0848 0.0016 0.0046 0.0106 0.0337 0.0029 0.0011 0.0117 0.9291 0.0370 0.0071 0.1351 0.2763 0.0004 0.0005 0.0006 0.2256 0.0004 0.0006 0.0007 0.0035 0.0007 0.0006 0.0008 0.0601 0.0005 0.0011 0.0009 0.0031
Abbreviations: ALX, low-frequency reactance area; CAT, COPD assessment test; CI, confidence interval; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEF25–75%, forced expiratory flow between 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; Fres, resonant frequency; FVC, forced vital capacity; IC, inspiratory capacity; mMRC, modified British Medical Research Council; R5 and R20, respiratory system resistance at 5 Hz and 20 Hz, respectively; X5, respiratory system reactance at 5 Hz. *p < 0.05 versus EFL-negative.
Table 3 Multivariate analysis for predictors of EFL-positivity. Variables
Adjusted odds ratio
95% CI
p-Value
Body mass index Emphysema score %FVC Whole-breath X5a
1.575 1.503 0.856 6.170
0.998–2.893 1.114–2.466 0.712–0.958 2.128–37.358
0.0799 0.0362 0.0328 0.0086
Abbreviations: CI, confidence interval; EFL, expiratory flow limitation; FVC, forced vital capacity; X5, respiratory system reactance at 5 Hz. a Shown as an absolute value.
Short-acting 2 agonists were not used for more than 12 h before these tests in every case. The protocols were approved by the Institutional Review Board of Shizuoka General Hospital (SGH 14-01-44) and written informed consent was obtained from all subjects prior to the study.
The mMRC scale was used to evaluate dyspnea in daily living, grading 0 (only get breathless with strenuous exercise) to 4 (too breathless to leave the house or breathless when dressing) (Bestall et al., 1999). The CAT (Japanese version, supplied by GlaxoSmithKline Japan) questionnaire consists of 8 items (cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity limitations at home, confidence leaving home, sleep, and energy) assessing and quantifying the symptoms and impacts of COPD (Jones et al., 2009). Each item is scored from 0 to 5 giving a total score range from 0 to 40, corresponding to the best and worst health status, respectively. 2.4. Measurement of respiratory impedance and pulmonary function tests Respiratory impedance was measured with broadband frequency FOT using a commercially available device (MostGraph-01; Chest M.I. Co., Ltd., Tokyo, Japan) and met standard recommendations (Oostveen et al., 2003). In this study, we used Rrs at 5 and 20 Hz (R5 and R20, respectively), and the difference between R5 and R20 (R5–R20) as an indicator of the frequency dependence of Rrs. We also used Xrs at 5 Hz (X5), which reflects elastic and inertial properties of the lung, resonant frequency (Fres) where Xrs crosses zero and the elastic and inertial forces are equal in magnitude and opposite, and a low-frequency reactance area (ALX), which is the integral of Xrs at 5 Hz to the Fres. Oscillatory indices were expressed as the mean values during a respiratory cycle (whole-breath), inspiratory and expiratory phases, and the differences between inspiratory and expiratory phases (), with colored 3-dimensional imaging patterns (Mori et al., 2011; Mikamo et al., 2014). Spirometry was performed using a computerized equipment (model CHESTAC-8800; Chest M.I. Co., Ltd., Tokyo, Japan) according to the recommendations (American Thoracic Society, 1995). Predicted values for pulmonary function tests were obtained from the Japanese Respiratory Society guidelines (Japanese Respiratory Society, 2004). 2.5. NEP The measurement of EFL was performed by the NEP technique using a commercially available pneumotachograph with a vacuum generator (Multi-Functional Spirometer HI-801; Chest M.I. Co., Ltd., Tokyo, Japan) according to methods described previously (Koulouris et al., 1995; Dellacà et al., 2007; Walker et al., 2007). Briefly, after a period of relaxed tidal breathing, an NEP of −5 cmH2 O was applied when expiratory flow reached a threshold value of 20 mL/s and was maintained throughout expiration. Expiratory flow-volume loops generated with NEP were superimposed on those obtained during the preceding tidal breaths. The pneumotachogram was continuously monitored during testing on the screen of a computer, and calibrations for flow and pressure were performed prior to each testing occasion. The NEP
Table 4 ROC curve analysis of X5-related forced oscillatory parameters for predicting EFL-positivity. Variables
Cut point
Sensitivity
Specificity
Area under the curve
95% CI
Whole-breath X5 Inspiratory X5 Expiratory X5 X5
−1.925 −1.405 −2.335 0.750
0.923 0.867 0.933 0.867
0.846 0.917 0.778 0.722
0.885 0.919 0.892 0.685
0.776–0.993 0.832–1.000 0.806–0.978 0.685–0.952
Abbreviations: CI, confidence interval; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; X5, respiratory system reactance at 5 Hz; ROC, receiver operator characteristic.
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technique was applied to all subjects in the sitting position with a nose clip worn. Three to five test breaths separated by periods of quiet breathing were performed by the patient. EFL was judged by 2 independent researchers who were experienced in the interpretation of NEP tests. Subjects in whom application of NEP did not elicit an increase in flow during part or all of the tidal expiration (Fig. 1, upper left) were considered EFL-positive. A transient increase in flow similar to a spike when NEP is applied is a marker of EFL (Koulouris et al., 2012). In other words, two lines overlapped throughout expiration, excluding the short and sharp spike of extra flow. In contrast, subjects in whom flow increased with NEP throughout the control tidal volume range (Fig. 1, lower left) were considered EFL-negative. In other words, there were no overlapping regions between the control expiratory trace and the NEP expiratory trace throughout expiration. Subjects in whom NEP did not elicit any increase in flow transiently or during the tidal expiration even after repeated maneuvers were excluded from the analysis (Fig. 1, lower right). The results were exclude if one or more of the following conditions was present. (1) The volume time course showed air leaks during the NEP application. (2) The duration of the NEP breath is not as long as that of the control breath. (3) The control and NEP loops are clearly different. (4) The flow trace shows wide oscillations during the application of NEP. 2.6. Emphysema score CT scans were performed with a helical CT system with a 64row detector (Aquilion; Toshiba, Tokyo, Japan). High-resolution computed tomography (HRCT) images consisted of 1-mm collimation sections, at 10-mm intervals, at end inspiration, taken in a supine position and reconstructed by a high-spatial-frequency algorithm. The images were obtained at window settings appropriate for viewing the lung parenchyma (window level from −600 to −800 Hounsfield units (HU) and window width from 1200 to 2000 HU). Intravenous constant medium was not used. Emphysema was evaluated by HRCT according to the method reported previously (Mori et al., 2013). HRCT images of the study patients were reviewed independently by 2 well-trained pulmonary physicians who were unaware of the clinical information and determined by consensus reading. In each patient, CT findings were evaluated at 3 anatomic levels in both lungs: near the superior margin of the aortic arch (level of the upper lung field), at the level of the carina (level of the middle lung field), and at the level of the orifice of the inferior pulmonary veins (level of the lower lung field). Emphysema was defined as a focal region of low attenuation without visible walls. Cysts were defined as round air spaces with a well-defined wall. Emphysema with cysts, if any, was scored visually in the 6 fields and summed. The score in each lung field was calculated according to the percentage of low-attenuation areas (%LAA): score 0, %LAA < 5%; score 1, %LAA ≥ 5% to <25%; score 2, %LAA ≥ 25–50%; score 3, %LAA ≥ 50–75%; and score 4, %LAA ≥ 75%. Assessment of the lung was at 3 levels. The highest fibrosis score was 4. This adds up to 12. Both lung were assessed. Thus, the total emphysema scores ranged from 0 to 24. 2.7. Statistical analysis Comparisons between groups were made using the Mann–Whitney U test. The chi-square or Fisher’s exact test was used to test significance in group differences with respect to the percentage of patients in various categories. Univariate and multivariate logistic regression analyses were performed to assess the predictors of EFL-positivity. Model selection was made by the best subset selection procedure using Akaike’s information criteria (AIC). A receiver-operator characteristic (ROC) curve was
Fig. 3. The ROC curve analysis of X5-related forced oscillatory parameters for predicting EFL-positivity. Abbreviations: , difference between inspiratory and expiratory phases; ROC, receiver operator characteristic; X5, respiratory system reactance at 5 Hz.
constructed to assess which of the X5-related forced oscillatory parameters would predict EFL-positivity. Stat View Version 5.0 (SAS Institute, Cary, NC, USA) and R version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria, 2012) were used for statistical calculations. A p value of <0.05 was considered significant, and all tests were 2-sided. 3. Results The clinical characteristics of the subjects are shown in Table 1. Of the total 63 patients with COPD, 15 were classified into the EFLpositive group and 36 into the EFL-negative group. Twelve patients were excluded from the analysis because results compatible with EFL-positive or EFL-negative were not obtained (Fig. 2). mMRC scale, emphysema score, and GOLD stages were significantly higher and FVC, FEV1, IC, FEF25-75% were lower in the EFL-positive group than in the EFL-negative group. R5 and R5–R20 (whole-breath, inspiratory, and expiratory), R20 (whole-breath and inspiratory), X5, and Fres and ALX (whole-breath, inspiratory, and expiratory) were significantly higher and X5 (whole-breath, inspiratory, and expiratory), Fres and ALX were lower in the EFL-positive group than in the EFL-negative group. There was no difference in age, gender, body mass index, smoking history, CAT, or medications used between the 2 groups. Univariate analysis revealed that mMRC scale, FVC, FEV1, FEF25–75%, IC, R5, R5–R20, X5, Fres, and ALX (whole-breath, inspiratory, and expiratory), R20 (whole-breath and inspiratory), X5, and ALX were significant predictors of EFL-positivity (Table 2). Multivariate logistic regression analysis of EFL-positivity was performed using the selected model including 4 variables (AIC 32.3, Table 3). The EFL-positivity was independently predicted by emphysema score, FVC, and whole-breath X5. Unlike univariate analysis, multivariate analysis revealed that severe emphysema related to EFL-positivity. The ROC curve analysis of X5-related forced oscillatory parameters are shown in Fig. 3 and Table 4. Area under the curve for inspiratory X5 was superior to other X5-related parameters for predicting EFL-positivity.
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4. Discussion We assessed whether broadband frequency FOT would predict the presence of EFL measured by NEP in 51 patients with COPD. In multivariate logistic regression analysis, it was found that EFL was independently predicted by emphysema score, FVC, and whole-breath X5. The ROC curve analysis revealed that inspiratory X5 of the X5-related forced oscillatory parameters best predicted EFL-positivity. These results suggest that X5-related oscillatory parameters are broadly useful for detecting EFL in the management of COPD. In a previous study (Dellacà et al., 2007), investigators analyzed 180 breaths by applying both monofrequency FOT at 5 Hz and NEP in a simultaneous measurement setup. They found that X5 classified 53.3% of the breaths as EFL-positive and 46.7% as EFL-negative, whereas NEP classified only 27.6% of the breaths as EFL-positive and 47.6% as EFL-negative, with the remaining 24.8% being unsuitable for NEP analysis. They used X5 as a forced oscillatory parameter to detect EFL according to their previous findings that X5 and the minimum expiratory X5 detected EFL, proven by esophageal manometry, with 100% sensitivity and specificity, which were better than expiratory X5 and the difference between maximum inspiratory X5 and minimum expiratory X5 (Dellacà et al., 2004). In this study, as an independent predictor of EFLpositivity whole-breath X5, instead of X5, was selected according to AIC, whereas the ROC curve analysis showed that inspiratory X5 best predicted the EFL-positivity. Possible explanations for the discrepancy may be the difference in the FOT devices used, and separate measurements of FOT and NEP in this study. Considering that whole-breath and inspiratory X5 and X5 are X5-related parameters in a broad sense, each parameter is thought to reflect the mechanical properties of airways proximal to the choke points during EFL. In the same previous study (Dellacà et al., 2007), 24.8% of the flow-volume loops were discarded because they did not meet the acceptance criteria. One reason for this was upper airways instability. Similarly, in this study, flow-volume loops suitable for analysis were not obtained in twelve of 63 initially enrolled patients. Both FOT and NEP are noninvasive and easily repeated. Since broadband frequency FOT in particular yields many oscillatory parameters automatically, EFL, regardless of whole-breath X5 or X5, can be evaluated in all patients. In contrast, the presence or absence of EFL in NEP depends on the judgement of observers. Thus, the clinical application of the FOT may be promising as a tool to detect EFL. We previously assessed which clinical parameters contributed to the degree of EFL (X5) measured by broadband frequency FOT in 74 patients with COPD and found that a high X5 (more than the median value of 0.55 cmH2 O/L/s) was independently predicted by the extent of emphysema as measured by HRCT, FEF25–75%, functional residual capacity, and whole-breath R5 (Mikamo et al., 2014). In this study, we also confirmed that the extent of emphysema and FVC were independent predictors of EFL measured by NEP, suggesting that reduced lung elastic recoil due to emphysema and air trapping or small airway function may be the causes of EFL. A review article stated that EFL in COPD is caused by airflow reduction, including increased airway resistance, augmented cholinergic bronchial tone, decreased lung elastance, airway-parenchyma uncoupling, and airways collapsibility (Tantucci, 2013). The FOT is a noninvasive method with which to measure respiratory impedance, the spectral relationship between pressure and airflow (Oostveen et al., 2003). The real part of impedance is called Rrs, whereas the imaginary part is called Xrs, which is supposed to reflect elastic and inertial properties of the lung. Rrs reflects the dissipative mechanical property of the lung, in other words, viscous resistance. As airway obstruction increases, Rrs rises, implying
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that Rrs is supposed to be a measure of airway caliber (Di Mango et al., 2006). In multivariate regression analyses, we found that X5 contributed significant to the differentiation between COPD and asthma, independent of age, gender, body weight, and pulmonary function (Mori et al., 2011). Since the FOT device used in this study could provide colored 3-dimensional images of respiratory impedance (Mori et al., 2011; Mikamo et al., 2014), the difference in the images between EFLpositive and EFL-negative patients was distinct. This technique enables rapid perception of the disease condition rather than comparing each value, and would be useful if applied more widely in real clinical practice. The major limitations of this study is the lack of direct assessment of EFL, i.e., recording of flow and transpulmonary pressure by using esophageal balloon technique, the gold standard technique in the true sense. Accordingly, it is difficult to derive strong conclusions when interpreting obtained data. However, our aim was to assess the usefulness of the FOT for detecting EFL measured by a conventional method. Furthermore, EFL in COPD patients is most relevant in supine position since in this posture EFL is considerably increased. The lack of measurements in supine position may lead to the relatively low percentage of patients with EFL. Since the FOT is usually performed in the sitting position, we needed to compare two techniques in the same conditions. In conclusion, EFL measured by NEP was independently predicted by the extent of emphysema, FVC, and whole-breath X5 in multivariate logistic regression analysis. The ROC curve analysis revealed that inspiratory X5 best predicted EFL-positivity. X5-related oscillatory parameters in a broad sense are useful for detecting EFL in the management of COPD. Funding None. References American Thoracic Society, 1995. Standardization of spirometry, 1994 update. Am. J. Respir. Crit. Care Med. 152, 107–1136. Bestall, J.C., Paul, E.A., Garrod, R., Garnham, R., Jones, P.W., Wedzicha, J.A., 1999. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 54, 581–586. Dellacà, R.L., Santus, P., Aliverti, A., Stevenson, N., Centanni, S., Macklem, P.T., Pedotti, A., Calverley, P.M., 2004. Detection of expiratory flow limitation in COPD using the forced oscillation technique. Eur. Respir. J. 23, 232–240. Dellacà, R.L., Duffy, N., Pompilio, P.P., Aliverti, A., Koulouris, N.G., Pedotti, A., Calverley, P.M., 2007. Expiratory flow limitation detected by forced oscillation and negative expiratory pressure. Eur. Respir. J. 29, 363–374. Di Mango, A.M., Lopes, A.J., Jansen, J.K., Melo, P.L., 2006. Changes in respiratory mechanics with increasing degrees of airway obstruction in COPD: detection by forced oscillation technique. Respir. Med. 100, 399–410. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.. Date last updated: 20.02.13. Date last accessed: (01.01.14.). Japanese Respiratory Society, 2004. Guidelines of Respiratory Function Tests: Spirometry, Flow-volume Curve, and Diffusion Capacity of the Lung (in Japanese). Japanese Respiratory Society, Tokyo. Jones, P.W., Harding, G., Berry, P., Wiklund, I., Chen, W.H., Leidy, N.K., 2009. Development and first validation of the COPD assessment test. Eur. Respir. J. 34, 648–654. Koulouris, N.G., Valta, P., Lavoie, A., Corbeil, C., Chassé, M., Braidy, J., Milic-Emili, J., 1995. A simple method to detect expiratory flow limitation during spontaneous breathing. Eur. Respir. J. 8, 306–313. Koulouris, N.G., Hardavella, G., 2011. Physiological techniques for detecting expiratory flow limitation during tidal breathing. Eur. Respir. Rev. 20, 147–155. Koulouris, N.G., Karltsakas, G., Palamidas, A.F., Gennimata, S.A., 2012. Methods for assessing expiratory flow limitation during tidal breathing in COPD patients. Pulm. Med., 234145. Mikamo, M., Shirai, T., Mori, K., Shishido, Y., Akita, T., Morita, S., Asada, K., Fujii, M., Suda, T., 2014. Predictors of expiratory flow limitation measured by forced oscillation technique in COPD. BMC Pulm. Med. 14, 23. Mori, K., Shirai, T., Mikamo, M., Shishido, Y., Akita, T., Morita, S., Asada, K., Fujii, M., Suda, T., Chida, K., 2011. Colored 3-dimensional analyses of respiratory resistance and reactance in COPD and asthma. COPD 8, 456–463.
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Mori, K., Shirai, T., Mikamo, M., Shishido, Y., Akita, T., Morita, S., Asada, K., Fujii, M., Hozumi, H., Suda, T., Chida, K., 2013. Respiratory mechanics measured by forced oscillation technique in combined pulmonary fibrosis and emphysema. Respir. Physiol. Neurobiol. 185, 235–240. Oostveen, E., Macleod, D., Lorino, H., Farré, R., Hantos, Z., Desager, K., Marchal, F., 2003. The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur. Respir. J. 22, 1026–1041.
Tantucci, C., 2013. Expiratory flow limitation definition, mechanisms, methods, and significance. Pulm. Med., http://dx.doi.org/10.1155/2013/749860, Article ID 749860. Walker, B., Paratz, J., Holland, A.E., 2007. Reproducibility of the negative expiratory pressure technique in COPD. Chest 132, 471–476.
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Association of the forced oscillation technique with negative expiratory pressure in COPD Takefumi Akita a , Toshihiro Shirai a,∗,1 , Kazutaka Mori b , Yukiko Shimoda a , Takahito Suzuki a , Ichiro Hayashi a , Rie Noguchi a , Eisuke Mochizuki a , Shogo Sakurai a , Mika Saigusa a , Taisuke Akamatsu a , Akito Yamamoto a , Yuichiro Shishido a , Satoru Morita a , Kazuhiro Asada a , Takafumi Suda b a b
Department of Respiratory Medicine, Shizuoka General Hospital, Shizuoka, Japan Second Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
a r t i c l e
i n f o
Article history: Received 28 August 2015 Received in revised form 8 September 2015 Accepted 10 September 2015 Available online 11 September 2015 Keywords: Expiratory flow limitation Forced oscillation technique Negative expiratory pressure Reactance Tidal breathing
a b s t r a c t Expiratory flow limitation (EFL) during tidal breathing is common in patients with severe COPD, and a major determinant of dynamic hyperinflation and exercise limitation. The negative expiratory pressure (NEP) technique has been the gold standard to detect EFL, while the forced oscillation technique (FOT) has also been reported to detect it. However, the association of FOT with NEP is not fully understood. We assessed whether broadband frequency FOT would predict the presence of EFL measured by NEP. FOT, NEP, and spirometry were performed in 51 patients with COPD. The extent of emphysema was measured by high-resolution computed tomography and scored. Fifteen patients were classified into the EFL-positive group and 36 into the EFL-negative group. In multivariate logistic regression analysis, EFL was independently predicted by emphysema score, forced vital capacity, and whole-breath respiratory system reactance at 5 Hz (X5). The receiver operator characteristic curve analysis revealed that inspiratory X5 best predicted EFL-positivity. X5-related forced oscillatory parameters are useful for detecting EFL in the management of COPD. © 2015 Published by Elsevier B.V.
1. Introduction
Abbreviations: AIC, Akaike’s information criteria; ALX, low-frequency reactance area; , differences between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEV1, forced expiratory volume in 1 s; FOT, forced oscillation technique; Fres, resonant frequency; FVC, forced vital capacity; HRCT, high-resolution computed tomography; NEP, negative expiratory pressure; ROC, receiver operator characteristic; Rrs, respiratory system resistance; R5, Rrs at 5 Hz; R20, Rrs at 20 Hz; R5-R20, the difference between R5 and R20; X5, Xrs at 5 Hz; Xrs, respiratory system reactance. ∗ Corresponding author at: Shizuoka General Hospital, 4-27-1 Kita-Ando, Aoi, Shizuoka 420−8527, Japan. Fax: +81 54 247 6140. E-mail addresses: [email protected] (T. Akita), [email protected] (T. Shirai), [email protected] (K. Mori), [email protected] (Y. Shimoda), [email protected] (T. Suzuki), [email protected] (I. Hayashi), [email protected] (R. Noguchi), [email protected] (E. Mochizuki), [email protected] (S. Sakurai), [email protected] (M. Saigusa), [email protected] (T. Akamatsu), akito [email protected] (A. Yamamoto), [email protected] (Y. Shishido), [email protected] (S. Morita), [email protected] (K. Asada), [email protected] (T. Suda). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.resp.2015.09.002 1569-9048/© 2015 Published by Elsevier B.V.
Some patients with COPD show overlapped flow-volume curves between tidal breathing and forced expiration. This phenomenon has been taken as an indicator of expiratory flow limitation (EFL), common in patients with severe COPD, and is a major determinant of dynamic hyperinflation and exercise limitation (Koulouris and Hardavella, 2011). EFL occurs when an increase in transpulmonary pressure causes no increase in expiratory flow. The negative expiratory pressure (NEP) technique has been the gold standard for detecting EFL (Koulouris et al., 2012). In the absence of EFL, the increase in pressure gradient between the alveoli and the airway opening caused by NEP results in increased expiratory flow, whereas in patients with EFL, application of NEP does not change the expiratory flow. This method is simple, noninvasive, and does not require forced expiration, collaboration on the part of the patient, or use of body plethysmography. As another approach, Dellacà et al. indicated that the differences between the inspiratory and expiratory phases of respiratory system reactance (Xrs) measured by the forced oscillation technique (FOT) allowed the detection of EFL (Dellacà et al., 2004). It is thought that Xrs normally reflects the elastic and inertial properties of the respiratory
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Fig. 1. Representative examples of flow-volume loops during the negative expiratory pressure (NEP) maneuver for expiratory flow limitation (EFL)-positive (upper left), EFL-negative (lower left), and excluded patients because of indeterminable results (lower right).
system, but with flow limitation, oscillatory signals cannot pass through the choke points and reach the alveoli. During EFL, respiratory system resistance (Rrs) and Xrs reflect the mechanical properties of airways proximal to the choke points, which are much stiffer than the periphery, producing a marked reduction in apparent compliance and a fall in Xrs. Subsequently, Dellacà et al. (2007)
reported a modest agreement between NEP and FOT by using an experimental setup for simultaneous measurements (Dellacà et al., 2007). To date, there has been no other study assessing the association of FOT with NEP. In contrast to the monofrequency FOT at 5 Hz used by Dellacà et al. (2007) clinical application of broadband frequency FOT has progressed recently with the spread of
Fig. 2. Colored 3-dimensional images of respiratory system resistance (Rrs) and respiratory system reactance (Xrs) in representative expiratory flow limitation (EFL)-positive (upper panel) and EFL-negative (lower panel) patients. Respiratory cycle dependence (Rrs was higher and Xrs was more negative in the expiratory phases than in the inspiratory phases) and frequency dependence (Rrs increased at lower frequencies and fell with increasing frequencies) were marked in the EFL-positive patients.
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Table 1 Characteristics of the subjects. Patients with COPD (n = 51)
EFL-positive (n = 15)
EFL-negative (n = 36)
Age (years) Gender (male/female) Body mass index (kg/m2 ) Current/ex/never smoker Pack-years mMRC scale CAT score Emphysema score GOLD I/II/III/IV LAMA LABA LAMA + LABA LAMA + ICS/LABA Sustained-release theophylline FVC (% predicted) FEV1 (% predicted) FEV1/FVC (%) FEF25-75% (% predicted) IC (L)
74 (65–84) 46/5 21.1 (15.1–29.1) 3/48/0/ 50 (2–180) 1 (0–5) 10 (1–35) 10 (2–22) 11/16/17/7 5 6 31 4 9 90.3 (38.3–128.1) 50.9 (16.2–114.2) 50.7 (21.4–68.4) 18.2 (4.9–51.1) 1.81 (0.75–3.03)
74 (67–84) 11/4 21.0 (15.1–29.0) 1/14/0 50 (2–180) 2 (0–5)* 11 (1–22) 12 (2–22)* 0/4/6/5* 1 2 11 1 4 71.6 (38.3–101.7)* 40.8 (16.2–77.3)* 42.9(21.4–64.5) 9.1 (4.9–42.5)* 1.63 (0.75–2.77)*
75 (65–84) 35/1 21.2 (16.2–29.1) 2/34/0 50 (10–150) 1 (0–4) 10 (2–35) 10 (2–22) 11/12/11/2 4 4 20 3 5 95.5 (50.3–128.1) 59.9(27.4–114.2) 52.5 (27.2–68.4) 21.4 (5.3–51.1) 1.95 (0.88–3.03)
R5 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory R5
3.72 (1.73–7.11) 3.35 (1.66–6.57) 4.21 (1.78–9.00) −0.71 (−3.78–0.93)
4.96 (2.70–7.11)* 4.42 (2.88–6.57)* 4.56 (2.52–9.00)* −0.78 (−3.78–0.93)
3.40 (1.73–5.96) 3.25 (1.66–5.46) 3.65 (1.78–7.05) -0.69 (-3.76–0.26)
R20 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory R20
2.74 (1.42–5.43) 2.59 (1.42–4.58) 2.87 (1.41–6.31) −0.27 (−2.17–0.71)
3.23 (1.83–5.43)* 3.29 (1.84–4.58)* 3.00 (1.83–6.31) −0.14 (−1.76–0.71)
2.58 (1.42–4.86) 2.45 (1.42–4.06) 2.80 (1.41–5.66) −0.40 (−2.17–0.23)
R5-R20 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory (R5–R20)
0.98 (0.13–2.38) 0.68 (0.03–2.03) 1.22 (0.22–2.76) −0.41 (−2.02–0.35)
1.55 (0.87–2.38)* 1.29 (0.65–1.99)* 1.81 (0.69–2.76)* −0.63 (−2.02–0.35)
0.80 (0.13–2.04) 0.55 (0.03–2.03) 1.02 (0.22–2.33) −0.35 (−1.59–0.16)
X5 (cmH2 O/L/s) Whole-breath Inspiratory Expiratory X5
−1.28 (−5.30–0.09) −1.06 (−3.13–0.01) −1.69 (−8.39–0.13) 0.51 (−0.79–6.44)
−2.97 (−5.30–1.54)* −1.95 (−2.94–0.74)* −3.38 (−8.39–1.85)* 1.61 (−0.25–6.44)*
−0.80 (−3.67–0.09) −0.76 (−3.13–0.01) −0.75 (−5.99–0.13) 0.14 (−0.79–4.63)
Fres (Hz) Whole-breath Inspiratory Expiratory Fres
14.83 (5.68–25.89) 12.29 (4.94–24.51) 16.63 (5.96–28.70) −2.72 (−14.95–5.57)
20.12 (14.88–25.89)* 19.10 (11.40–23.57)* 22.65 (16.24–28.70)* −4.52 (−11.75–0.24)*
11.60 (5.68–24.25) 11.47 (4.94–24.51) 11.51 (5.96–26.84) −1.37 (−14.95–5.57)
ALX (cmH2 O/L/s x Hz) Whole-breath Inspiratory Expiratory ALX
7.85 (0.35–48.57) 5.31 (0.16–30.08) 11.11 (0.40–77.23) −3.57 (−66.18–5.03)
22.86 (9.34–48.57)* 12.46 (3.50–25.91)* 28.21 (11.87–77.23)* −14.17 (−66.13–1.08)*
3.76 (0.35–31.86) 3.37 (0.16–30.08) 3.43 (0.40–50.54) −0.70 (−42.26–5.03)
Values are shown as the median (range) or numbers. Abbreviations: ALX, low-frequency reactance area; CAT, COPD assessment test; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEF25-75%, forced expiratory flow between 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; Fres, resonant frequency; FVC, forced vital capacity; GOLD, Global Initiative for Chronic Obstructive Lung Disease; IC, inspiratory capacity; ICS, inhaled corticosteroids; LABA, long-acting 2-agonists; LAMA, long-acting antimuscarinic agents; mMRC, modified British Medical Research Council; R5 and R20, respiratory system resistance at 5 ; X5, respiratory system reactance at 5 Hz. * p < 0.05 versus EFL-negative.
commercially available devices. We hypothesized that broadband frequency FOT would predict the presence of EFL measured by NEP. In this cross-sectional study, we assessed the association of FOT with NEP in patients with COPD. 2. Methods
Obstructive Lung Disease (GOLD, 2013) and had been receiving medications, including long-acting antimuscarinic agents, longacting 2-agonists, inhaled corticosteroids, or sustained-release theophylline. They were clinically stable and had no exacerbations, defined as increased dyspnea associated with a change in the quality and quantity of sputum, for at least one month before the study.
2.1. Subjects 2.2. Study design Sixty-three patients with COPD who attended outpatient clinics at Shizuoka General Hospital for routine check-ups between January 2014 and January 2015 were enrolled in this study. The patients satisfied the definition of the Global Initiative for Chronic
On the same examination day, when their clinical symptoms were stable, measurements of respiratory impedance using FOT, NEP, and pulmonary function tests were performed in that order.
T. Akita et al. / Respiratory Physiology & Neurobiology 220 (2016) 62–68 Table 2 Univariate analysis for predictors of EFL-positivity.
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2.3. Modified Medical Research Council (mMRC) and COPD assessment test (CAT)
Variables
Odds ratio
95% CI
p-Value
Age (years) Body mass index (kg/m2 ) Pack-years mMRC scale CAT score Emphysema score %FVC (% predicted) %FEV1 (% predicted) FEF25–75% (% predicted) IC (L) Whole-breath R5 (cmH2 O/L/s) Inspiratory R5 (cmH2 O/L/s) Expiratory R5 (cmH2 O/L/s) R5 (cmH2 O/L/s) Whole-breath R20 (cmH2 O/L/s) Inspiratory R20 (cmH2 O/L/s) Expiratory R20 (cmH2 O/L/s) R20 (cmH2 O/L/s) Whole-breath R5–R20 (cmH2 O/L/s) Inspiratory R5–R20 (cmH2 O/L/s) Expiratory R5–R20 (cmH2 O/L/s) (R5–R20) (cmH2 O/L/s) Whole-breath X5 (cmH2 O/L/s) Inspiratory X5 (cmH2 O/L/s) Expiratory X5 (cmH2 O/L/s) X5 (cmH2 O/L/s) Fres (Hz) Inspiratory Fres (Hz) Expiratory Fres (Hz) Fres (Hz) ALX (cmH2 O/L/s x Hz) Inspiratory ALX (cmH2 O/L/s x Hz) Expiratory ALX (cmH2 O/L/s x Hz) ALX (cmH2 O/L/s x Hz)
1.006 1.575 1.003 1.913 1.016 1.110 0.928 0.943 0.906 0.243 2.371 3.656 1.694 1.029 2.049 3.272 1.497 1.910 40.902 24.036 13.877 0.444 0.225 0.071 0.437 2.010 1.475 1.415 1.329 0.868 1.160 1.266 1.087 0.933
0.894–1.132 0.998–2.893 0.986–1.020 1.112–3.588 0.935–1.102 0.990–1.259 0.879–0.966 0.900–0.977 0.829–0.968 0.057–0.816 1.414–4.499 1.844–9.045 1.153–2.654 0.552–2.026 1.073–4.233 1.468–8.524 0.888–2.614 0.652–7.092 7.086–457.026 4.958–194.777 3.745–82.651 0.109–1.632 0.083–0.453 0.011–0.246 0.248–0.659 1.317–3.428 1.223–1.943 1.192–1.794 1.155–1.629 0.740–1.001 1.080–1.283 1.125–1.510 1.042–1.152 0.885–0.972
0.9221 0.0799 0.6886 0.0269 0.6884 0.0848 0.0016 0.0046 0.0106 0.0337 0.0029 0.0011 0.0117 0.9291 0.0370 0.0071 0.1351 0.2763 0.0004 0.0005 0.0006 0.2256 0.0004 0.0006 0.0007 0.0035 0.0007 0.0006 0.0008 0.0601 0.0005 0.0011 0.0009 0.0031
Abbreviations: ALX, low-frequency reactance area; CAT, COPD assessment test; CI, confidence interval; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; FEF25–75%, forced expiratory flow between 25% and 75% of FVC; FEV1, forced expiratory volume in 1 s; Fres, resonant frequency; FVC, forced vital capacity; IC, inspiratory capacity; mMRC, modified British Medical Research Council; R5 and R20, respiratory system resistance at 5 Hz and 20 Hz, respectively; X5, respiratory system reactance at 5 Hz. *p < 0.05 versus EFL-negative.
Table 3 Multivariate analysis for predictors of EFL-positivity. Variables
Adjusted odds ratio
95% CI
p-Value
Body mass index Emphysema score %FVC Whole-breath X5a
1.575 1.503 0.856 6.170
0.998–2.893 1.114–2.466 0.712–0.958 2.128–37.358
0.0799 0.0362 0.0328 0.0086
Abbreviations: CI, confidence interval; EFL, expiratory flow limitation; FVC, forced vital capacity; X5, respiratory system reactance at 5 Hz. a Shown as an absolute value.
Short-acting 2 agonists were not used for more than 12 h before these tests in every case. The protocols were approved by the Institutional Review Board of Shizuoka General Hospital (SGH 14-01-44) and written informed consent was obtained from all subjects prior to the study.
The mMRC scale was used to evaluate dyspnea in daily living, grading 0 (only get breathless with strenuous exercise) to 4 (too breathless to leave the house or breathless when dressing) (Bestall et al., 1999). The CAT (Japanese version, supplied by GlaxoSmithKline Japan) questionnaire consists of 8 items (cough, phlegm, chest tightness, breathlessness going up hills/stairs, activity limitations at home, confidence leaving home, sleep, and energy) assessing and quantifying the symptoms and impacts of COPD (Jones et al., 2009). Each item is scored from 0 to 5 giving a total score range from 0 to 40, corresponding to the best and worst health status, respectively. 2.4. Measurement of respiratory impedance and pulmonary function tests Respiratory impedance was measured with broadband frequency FOT using a commercially available device (MostGraph-01; Chest M.I. Co., Ltd., Tokyo, Japan) and met standard recommendations (Oostveen et al., 2003). In this study, we used Rrs at 5 and 20 Hz (R5 and R20, respectively), and the difference between R5 and R20 (R5–R20) as an indicator of the frequency dependence of Rrs. We also used Xrs at 5 Hz (X5), which reflects elastic and inertial properties of the lung, resonant frequency (Fres) where Xrs crosses zero and the elastic and inertial forces are equal in magnitude and opposite, and a low-frequency reactance area (ALX), which is the integral of Xrs at 5 Hz to the Fres. Oscillatory indices were expressed as the mean values during a respiratory cycle (whole-breath), inspiratory and expiratory phases, and the differences between inspiratory and expiratory phases (), with colored 3-dimensional imaging patterns (Mori et al., 2011; Mikamo et al., 2014). Spirometry was performed using a computerized equipment (model CHESTAC-8800; Chest M.I. Co., Ltd., Tokyo, Japan) according to the recommendations (American Thoracic Society, 1995). Predicted values for pulmonary function tests were obtained from the Japanese Respiratory Society guidelines (Japanese Respiratory Society, 2004). 2.5. NEP The measurement of EFL was performed by the NEP technique using a commercially available pneumotachograph with a vacuum generator (Multi-Functional Spirometer HI-801; Chest M.I. Co., Ltd., Tokyo, Japan) according to methods described previously (Koulouris et al., 1995; Dellacà et al., 2007; Walker et al., 2007). Briefly, after a period of relaxed tidal breathing, an NEP of −5 cmH2 O was applied when expiratory flow reached a threshold value of 20 mL/s and was maintained throughout expiration. Expiratory flow-volume loops generated with NEP were superimposed on those obtained during the preceding tidal breaths. The pneumotachogram was continuously monitored during testing on the screen of a computer, and calibrations for flow and pressure were performed prior to each testing occasion. The NEP
Table 4 ROC curve analysis of X5-related forced oscillatory parameters for predicting EFL-positivity. Variables
Cut point
Sensitivity
Specificity
Area under the curve
95% CI
Whole-breath X5 Inspiratory X5 Expiratory X5 X5
−1.925 −1.405 −2.335 0.750
0.923 0.867 0.933 0.867
0.846 0.917 0.778 0.722
0.885 0.919 0.892 0.685
0.776–0.993 0.832–1.000 0.806–0.978 0.685–0.952
Abbreviations: CI, confidence interval; , difference between inspiratory and expiratory phases; EFL, expiratory flow limitation; X5, respiratory system reactance at 5 Hz; ROC, receiver operator characteristic.
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technique was applied to all subjects in the sitting position with a nose clip worn. Three to five test breaths separated by periods of quiet breathing were performed by the patient. EFL was judged by 2 independent researchers who were experienced in the interpretation of NEP tests. Subjects in whom application of NEP did not elicit an increase in flow during part or all of the tidal expiration (Fig. 1, upper left) were considered EFL-positive. A transient increase in flow similar to a spike when NEP is applied is a marker of EFL (Koulouris et al., 2012). In other words, two lines overlapped throughout expiration, excluding the short and sharp spike of extra flow. In contrast, subjects in whom flow increased with NEP throughout the control tidal volume range (Fig. 1, lower left) were considered EFL-negative. In other words, there were no overlapping regions between the control expiratory trace and the NEP expiratory trace throughout expiration. Subjects in whom NEP did not elicit any increase in flow transiently or during the tidal expiration even after repeated maneuvers were excluded from the analysis (Fig. 1, lower right). The results were exclude if one or more of the following conditions was present. (1) The volume time course showed air leaks during the NEP application. (2) The duration of the NEP breath is not as long as that of the control breath. (3) The control and NEP loops are clearly different. (4) The flow trace shows wide oscillations during the application of NEP. 2.6. Emphysema score CT scans were performed with a helical CT system with a 64row detector (Aquilion; Toshiba, Tokyo, Japan). High-resolution computed tomography (HRCT) images consisted of 1-mm collimation sections, at 10-mm intervals, at end inspiration, taken in a supine position and reconstructed by a high-spatial-frequency algorithm. The images were obtained at window settings appropriate for viewing the lung parenchyma (window level from −600 to −800 Hounsfield units (HU) and window width from 1200 to 2000 HU). Intravenous constant medium was not used. Emphysema was evaluated by HRCT according to the method reported previously (Mori et al., 2013). HRCT images of the study patients were reviewed independently by 2 well-trained pulmonary physicians who were unaware of the clinical information and determined by consensus reading. In each patient, CT findings were evaluated at 3 anatomic levels in both lungs: near the superior margin of the aortic arch (level of the upper lung field), at the level of the carina (level of the middle lung field), and at the level of the orifice of the inferior pulmonary veins (level of the lower lung field). Emphysema was defined as a focal region of low attenuation without visible walls. Cysts were defined as round air spaces with a well-defined wall. Emphysema with cysts, if any, was scored visually in the 6 fields and summed. The score in each lung field was calculated according to the percentage of low-attenuation areas (%LAA): score 0, %LAA < 5%; score 1, %LAA ≥ 5% to <25%; score 2, %LAA ≥ 25–50%; score 3, %LAA ≥ 50–75%; and score 4, %LAA ≥ 75%. Assessment of the lung was at 3 levels. The highest fibrosis score was 4. This adds up to 12. Both lung were assessed. Thus, the total emphysema scores ranged from 0 to 24. 2.7. Statistical analysis Comparisons between groups were made using the Mann–Whitney U test. The chi-square or Fisher’s exact test was used to test significance in group differences with respect to the percentage of patients in various categories. Univariate and multivariate logistic regression analyses were performed to assess the predictors of EFL-positivity. Model selection was made by the best subset selection procedure using Akaike’s information criteria (AIC). A receiver-operator characteristic (ROC) curve was
Fig. 3. The ROC curve analysis of X5-related forced oscillatory parameters for predicting EFL-positivity. Abbreviations: , difference between inspiratory and expiratory phases; ROC, receiver operator characteristic; X5, respiratory system reactance at 5 Hz.
constructed to assess which of the X5-related forced oscillatory parameters would predict EFL-positivity. Stat View Version 5.0 (SAS Institute, Cary, NC, USA) and R version 2.15.2 (R Foundation for Statistical Computing, Vienna, Austria, 2012) were used for statistical calculations. A p value of <0.05 was considered significant, and all tests were 2-sided. 3. Results The clinical characteristics of the subjects are shown in Table 1. Of the total 63 patients with COPD, 15 were classified into the EFLpositive group and 36 into the EFL-negative group. Twelve patients were excluded from the analysis because results compatible with EFL-positive or EFL-negative were not obtained (Fig. 2). mMRC scale, emphysema score, and GOLD stages were significantly higher and FVC, FEV1, IC, FEF25-75% were lower in the EFL-positive group than in the EFL-negative group. R5 and R5–R20 (whole-breath, inspiratory, and expiratory), R20 (whole-breath and inspiratory), X5, and Fres and ALX (whole-breath, inspiratory, and expiratory) were significantly higher and X5 (whole-breath, inspiratory, and expiratory), Fres and ALX were lower in the EFL-positive group than in the EFL-negative group. There was no difference in age, gender, body mass index, smoking history, CAT, or medications used between the 2 groups. Univariate analysis revealed that mMRC scale, FVC, FEV1, FEF25–75%, IC, R5, R5–R20, X5, Fres, and ALX (whole-breath, inspiratory, and expiratory), R20 (whole-breath and inspiratory), X5, and ALX were significant predictors of EFL-positivity (Table 2). Multivariate logistic regression analysis of EFL-positivity was performed using the selected model including 4 variables (AIC 32.3, Table 3). The EFL-positivity was independently predicted by emphysema score, FVC, and whole-breath X5. Unlike univariate analysis, multivariate analysis revealed that severe emphysema related to EFL-positivity. The ROC curve analysis of X5-related forced oscillatory parameters are shown in Fig. 3 and Table 4. Area under the curve for inspiratory X5 was superior to other X5-related parameters for predicting EFL-positivity.
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4. Discussion We assessed whether broadband frequency FOT would predict the presence of EFL measured by NEP in 51 patients with COPD. In multivariate logistic regression analysis, it was found that EFL was independently predicted by emphysema score, FVC, and whole-breath X5. The ROC curve analysis revealed that inspiratory X5 of the X5-related forced oscillatory parameters best predicted EFL-positivity. These results suggest that X5-related oscillatory parameters are broadly useful for detecting EFL in the management of COPD. In a previous study (Dellacà et al., 2007), investigators analyzed 180 breaths by applying both monofrequency FOT at 5 Hz and NEP in a simultaneous measurement setup. They found that X5 classified 53.3% of the breaths as EFL-positive and 46.7% as EFL-negative, whereas NEP classified only 27.6% of the breaths as EFL-positive and 47.6% as EFL-negative, with the remaining 24.8% being unsuitable for NEP analysis. They used X5 as a forced oscillatory parameter to detect EFL according to their previous findings that X5 and the minimum expiratory X5 detected EFL, proven by esophageal manometry, with 100% sensitivity and specificity, which were better than expiratory X5 and the difference between maximum inspiratory X5 and minimum expiratory X5 (Dellacà et al., 2004). In this study, as an independent predictor of EFLpositivity whole-breath X5, instead of X5, was selected according to AIC, whereas the ROC curve analysis showed that inspiratory X5 best predicted the EFL-positivity. Possible explanations for the discrepancy may be the difference in the FOT devices used, and separate measurements of FOT and NEP in this study. Considering that whole-breath and inspiratory X5 and X5 are X5-related parameters in a broad sense, each parameter is thought to reflect the mechanical properties of airways proximal to the choke points during EFL. In the same previous study (Dellacà et al., 2007), 24.8% of the flow-volume loops were discarded because they did not meet the acceptance criteria. One reason for this was upper airways instability. Similarly, in this study, flow-volume loops suitable for analysis were not obtained in twelve of 63 initially enrolled patients. Both FOT and NEP are noninvasive and easily repeated. Since broadband frequency FOT in particular yields many oscillatory parameters automatically, EFL, regardless of whole-breath X5 or X5, can be evaluated in all patients. In contrast, the presence or absence of EFL in NEP depends on the judgement of observers. Thus, the clinical application of the FOT may be promising as a tool to detect EFL. We previously assessed which clinical parameters contributed to the degree of EFL (X5) measured by broadband frequency FOT in 74 patients with COPD and found that a high X5 (more than the median value of 0.55 cmH2 O/L/s) was independently predicted by the extent of emphysema as measured by HRCT, FEF25–75%, functional residual capacity, and whole-breath R5 (Mikamo et al., 2014). In this study, we also confirmed that the extent of emphysema and FVC were independent predictors of EFL measured by NEP, suggesting that reduced lung elastic recoil due to emphysema and air trapping or small airway function may be the causes of EFL. A review article stated that EFL in COPD is caused by airflow reduction, including increased airway resistance, augmented cholinergic bronchial tone, decreased lung elastance, airway-parenchyma uncoupling, and airways collapsibility (Tantucci, 2013). The FOT is a noninvasive method with which to measure respiratory impedance, the spectral relationship between pressure and airflow (Oostveen et al., 2003). The real part of impedance is called Rrs, whereas the imaginary part is called Xrs, which is supposed to reflect elastic and inertial properties of the lung. Rrs reflects the dissipative mechanical property of the lung, in other words, viscous resistance. As airway obstruction increases, Rrs rises, implying
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that Rrs is supposed to be a measure of airway caliber (Di Mango et al., 2006). In multivariate regression analyses, we found that X5 contributed significant to the differentiation between COPD and asthma, independent of age, gender, body weight, and pulmonary function (Mori et al., 2011). Since the FOT device used in this study could provide colored 3-dimensional images of respiratory impedance (Mori et al., 2011; Mikamo et al., 2014), the difference in the images between EFLpositive and EFL-negative patients was distinct. This technique enables rapid perception of the disease condition rather than comparing each value, and would be useful if applied more widely in real clinical practice. The major limitations of this study is the lack of direct assessment of EFL, i.e., recording of flow and transpulmonary pressure by using esophageal balloon technique, the gold standard technique in the true sense. Accordingly, it is difficult to derive strong conclusions when interpreting obtained data. However, our aim was to assess the usefulness of the FOT for detecting EFL measured by a conventional method. Furthermore, EFL in COPD patients is most relevant in supine position since in this posture EFL is considerably increased. The lack of measurements in supine position may lead to the relatively low percentage of patients with EFL. Since the FOT is usually performed in the sitting position, we needed to compare two techniques in the same conditions. In conclusion, EFL measured by NEP was independently predicted by the extent of emphysema, FVC, and whole-breath X5 in multivariate logistic regression analysis. The ROC curve analysis revealed that inspiratory X5 best predicted EFL-positivity. X5-related oscillatory parameters in a broad sense are useful for detecting EFL in the management of COPD. Funding None. References American Thoracic Society, 1995. Standardization of spirometry, 1994 update. Am. J. Respir. Crit. Care Med. 152, 107–1136. Bestall, J.C., Paul, E.A., Garrod, R., Garnham, R., Jones, P.W., Wedzicha, J.A., 1999. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 54, 581–586. Dellacà, R.L., Santus, P., Aliverti, A., Stevenson, N., Centanni, S., Macklem, P.T., Pedotti, A., Calverley, P.M., 2004. Detection of expiratory flow limitation in COPD using the forced oscillation technique. Eur. Respir. J. 23, 232–240. Dellacà, R.L., Duffy, N., Pompilio, P.P., Aliverti, A., Koulouris, N.G., Pedotti, A., Calverley, P.M., 2007. Expiratory flow limitation detected by forced oscillation and negative expiratory pressure. Eur. Respir. J. 29, 363–374. Di Mango, A.M., Lopes, A.J., Jansen, J.K., Melo, P.L., 2006. Changes in respiratory mechanics with increasing degrees of airway obstruction in COPD: detection by forced oscillation technique. Respir. Med. 100, 399–410. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.
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